Substituted biphenyl derivatives

ABSTRACT

The invention relates to compounds of the formula I  
                 
 
     in which R 1 , R 2 , R 3 , R 4  and X have the meaning indicated in the text. The compounds act as inhibitors of factors Xa and VIIa and can therefore be employed for the control and prevention of thromboembolic conditions such as thrombosis, myocardial infarct, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.

[0001] The invention relates to compounds of the formula I

[0002] in which:

[0003] R¹ is: phenyl or naphthyl, which is substituted by —C(═NH)NH₂,that can also be monosubstituted by —COA, —CO—[C(R⁷)₂]_(n)—Ar′, —COOA,—OR⁷, —OCOA, —OCO—[C(R⁷)₂]_(n)—Ar′ or by a conventional amino protectivegroup, —NHC(═NH)—NH₂, —CON═C(NH₂)₂,

[0004] and which can optionally be substituted by -A, —OR⁵, —N(R⁵)₂,—NO₂, —CN, -Hal, —NR⁵COA, —NR⁵COAr′, —NR⁵SO₂A, —NR⁵SO₂Ar′, —COOR⁵,—CON(R⁵)₂, —COR⁷, —COAr′ or S(O)_(n)A;

[0005] R² is: —S(O)_(n)A, —CF₃, —COOR⁷, —OA;

[0006] R³, R⁴ are: independently of one another —H, -A, —OR⁵, —N(R⁵)₂,—NO₂, —CN, -Hal, —NR⁵COA, —NR⁵COAr′, —NR⁵SO₂A, —NR⁵SO₂Ar′, —COOR⁵,—CON(R⁵)₂, —CONR⁵Ar′, —COR⁷, —COAr′, —S(O)_(n)A;

[0007] R⁵, R⁶ are: independently of one another —H, -A,—[C(R⁷R⁸)]_(n)Ar′ or —[C(R⁷R⁸)]_(n)Het;

[0008] R⁷, R⁸ are: independently of one another —H or -A;

[0009] W is: —[C(R⁵R⁶)]mCONR5[C(R⁵R⁶)]_(l)—,—OC(R⁵R⁶)_(m)CONR⁵[C(R⁵R⁶)]_(l)—;

[0010] A is: alkyl having 1 to 20 C atoms, in which one or two CH₂groups can be replaced by O or S atoms or by —CH═CH— groups and also 1to 7 H atoms can be replaced by —F;

[0011] Ar is: phenyl or naphthyl, unsubstituted or mono-, di- ortrisubstituted by -A, —Ar′—, -Het, —OR⁵, —N(R⁵)₂, —NO₂, —CN, -Hal,—NR⁵COA, —NR⁵COAr, —NR⁵SO₂A, —NR⁵SO₂Ar′, —COOR⁵, —CON(R⁵)₂, —CONR⁵Ar′,—COR⁷, —COAr′, —SO₂NR⁵, —S(O)Ar′ or —S(O)_(n)A;

[0012] Ar′ is: phenyl or naphthyl, unsubstituted or mono-, di- ortrisubstituted by -A, —OR⁷, —N(R⁷)₂, —NO₂, —CN, -Hal, —NR⁷COA, —NR⁷SO₂A,—COOR⁷, —CON(R⁷)₂, —COR⁷, —SO₂NR⁷ or —S(O)_(n)A;

[0013] Het is: a mono- or binuclear saturated, unsaturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms, bonded via N or C, whichcan be unsubstituted or mono-, di- or trisubstituted by -A, —OR⁷,—N(R⁷)₂, —NO₂, —CN, -Hal, —NR⁷COA, —NR⁷SO₂A, —COOR⁷, —CON(R⁷)₂, —COR⁷,—SO₂NR⁷, —S(O)_(n)A and/or carbonyl oxygen;

[0014] Hal is: —F, —Cl, —Br or —I;

[0015] l is: 0 or 1;

[0016] m is: 1, 2 or 3;

[0017] n is: 0, 1 or 2;

[0018] and their pharmaceutically tolerable salts and solvates.

[0019] The invention also relates to the optically active forms, theracemates, the diastereomers and the hydrates and solvates, e.g.alcoholates, of these compounds.

[0020] The invention is based on the object of discovering novelcompounds having valuable properties, in particular those which can beused for the preparation of medicaments.

[0021] It has been found that the compounds of the formula I and theirsalts have very valuable pharmacological properties together with goodtolerability. In particular, they show factor Xa-inhibiting propertiesand can therefore be employed for the control and prevention ofthromboembolic conditions such as thrombosis, myocardial infarct,arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosisafter angioplasty and intermittent claudication.

[0022] The compounds of the formula I according to the invention canfurthermore be inhibitors of the clotting factors factor VIIa, factorIXa and thrombin of the blood-clotting cascade.

[0023] Compounds which act as inhibitors on factor Xa are described, forexample, in EP 540 051, WO 96/10022, WO 97/08165, WO 96/40679 and WO98/28282. The antithrombotic and anticoagulant effect of the compoundsaccording to the invention is attributed to the inhibitory actionagainst the activated clotting protease, known under the name factor Xa,or to the inhibition of other activated serine proteases such as factorVIIa, factor IXa or thrombin.

[0024] Factor Xa is one of the proteases which is involved in thecomplex process of blood clotting. Factor Xa catalyses the conversion ofprothrombin into thrombin. Thrombin cleaves fibrinogen into fibrinmonomers, which contribute elementarily to thrombus formation aftercrosslinkage. Activation of thrombin can lead to the occurrence ofthromboembolic conditions. Inhibition of thrombin, however, can inhibitthe fibrin formation involved in thrombus formation.

[0025] Measurement of the inhibition of thrombin can be carried out, forexample, according to the method of G. F. Cousins et al. in Circulation1996, 94,1705-1712.

[0026] Inhibition of factor Xa can thus prevent thrombin being formed.

[0027] The compounds of the formula I according to the invention andtheir salts intervene by inhibition of factor Xa in the blood-clottingprocess and thus inhibit the formation of thrombi.

[0028] The inhibition of factor Xa by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined according to customary in vitro or in vivomethods. A suitable process is described, for example, by J. Hauptmannet al. in Thrombosis and Haemostasis 1990, 63, 220-223.

[0029] The measurement of the inhibition of factor Xa can be carriedout, for example, according to the method of T. Hara et al. in Thromb.Haemostas. 1994, 71, 314-319. After binding to tissue factor, theclotting factor VIIa initiates the extrinsic part of the clottingcascade and contributes to the activation of factor X to factor Xa.Inhibition of factor VIIa thus prevents the formation of factor Xa andthus subsequent thrombin formation.

[0030] The inhibition of factor VIIa by the compounds according to theinvention and the measurement of the antocoagulant and antithromboticactivity can be determined by customary in vitro or in vivo methods.Customary procedure for measurement of the inhibition of factor VIIa isdescribed, for example, by H. F. Ronning et al. in Thrombosis Research1996, 84, 73-81.

[0031] The clotting factor IXa is generated in the intrinsic clottingcascade and is likewise involved in the activation of factor X to factorXa. Inhibition of factor IXa can therefore prevent factor Xa beingformed, in a different way.

[0032] The inhibition of factor IXa by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be carried out by customary in vitro or in vivo methods. Asuitable procedure is described, for example, by J. Chang et al. inJournal of Biological Chemistry 1998, 273, 12089-12094.

[0033] The compounds of the formula I can be employed aspharmaceutically active compounds in human and veterinary medicine, inparticular for the control and prevention of thromboembolic conditionssuch as thrombosis, myocardial infarct, arteriosclerosis, inflammation,apoplexy, angina pectoris, restenosis after angioplasty and intermittentclaudication.

[0034] The following compounds are of particular importance:

[0035]2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)acetamide(1),

[0036]2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)butyramide(2),

[0037] 2-(3-carbamimidoylphenoxy)pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (3),

[0038] (S)-2-(3-carbamimidoylphenoxy)pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (4),

[0039] (R)-2-(3-carbamimidoylphenoxy)pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (5),

[0040] (2-(3-carbamimidoylphenoxy)pentanoic acid(2′-ethanesulfonylbiphenyl-4-yl)amide (6),

[0041] (2-(3-carbamimidoylphenoxy)hexanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (7),

[0042] (2-(3-carbamimidoylphenoxy)heptanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (8),

[0043]2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)-3-methylbutyramide(9),

[0044] 2-(3-carbamimidoylphenoxy)-4-methylpentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (10),

[0045] 2-(3-carbamimidoylphenoxy)-4-methylpentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (11),

[0046]2-(3-carbamimidoylphenoxy)-N-(2′-ethanesulfonylbiphenyl-4-yl)-2-phenylacetamide(12),

[0047]2-(1,3-benzodioxol-5-yl)-2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)acetamide(13),

[0048]2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)-4-phenylbutyramide(14),

[0049] 2-(3-carbamimidoylphenoxy)pentanoic acid(2′-methanesulfonylbiphenyl-4-ylmethyl)amide (15),

[0050] 2-(3-carbamimidoylphenoxy)-4-methylpentanoic acid(2′-methanesulfonylbiphenyl-4-ylmethyl)amide (16);

[0051]2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-ylmethyl)-2-phenylacetamide(17),

[0052]3-(3-carbamimidoylphenyl)-N-(2′-methanesulfonylbiphenyl-4-yl)propionamide(18),

[0053] 2-(3-carbamimidoylbenzyl)pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (19),

[0054]3-(3-carbamimidoylphenyl)-N-(2′-methanesulfonylbiphenyl-4-yl)-2-phenylpropionamide(20),

[0055]3-(3-carbamimidoylphenyl)-N-(2′-ethanesulfonylbiphenyl-4-yl)-2-phenylpropionamide(21),

[0056]3-(3-carbamimidoylphenyl)-N-(2′-ethanesulfonylbiphenyl-4-yl)-2-(3-methoxyphenyl)propionamide(22),

[0057]2-benzyl-3-(3-carbamimidoylphenyl)-N-(2′-methanesulfonylbiphenyl-4-yl)propionamide(23),

[0058]2-benzyl-3-(3-carbamimidoylphenyl)-N-(2′-ethanesulfonylbiphenyl-4-yl)propionamide(24),

[0059]2-(3-carbaminidoylbenzyl)-N-(2′-methanesulfonylbiphenyl-4-yl)butyramide(25),

[0060] 2-(3-carbaminidoylbenzyl)hexanoicacid(2′-methanesulfonylbiphenyl-4-yl)amide (26),

[0061] 2-(3-carbamimidoyl)-4-methylpentanoicacid(2′-methanesulfonylbiphenyl-4-yl)amide (27),

[0062] methyl(1-imino-1-(3-(1-(2′-methanesulfonylbiphenyl-4-ylcarbamoyl)butoxy)phenyl)methyl)carbamate(28),

[0063] 2-(3-carbamimidoylphenoxy)pentanoicacid(2′-methoxybiphenyl-4-yl)amide (29),

[0064] 2-[3-(N-hydroxycarbamimidoyl)phenoxy]pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (30),

[0065] 2-(3-carbamimidoylphenoxy)pentanoicacid(2′-trifluoromethylbiphenyl-4-yl)amide (31).

[0066]ethyl(1-imino-1-{3-[1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate(32),

[0067] 2-[3-(N-pentanoyloxycarbamimidoyl)phenoxy]pentanoicacid-(2′-methansulfonylbiphenyl-4-yl)amide (33),

[0068] 2-[3-(N-(2-methylpropionyloxy)carbamimidoyl)phenoxyl]pentanoicacid (2′-methansulfonylbiphenyl-4-yl)amide (34),

[0069] 2-[3-(N-benzoyloxycarbamimidoyl)phenoxyl]pentanoicacid(2′-methansulfonylbiphenyl-4-yl)amide (35),

[0070] 2-[3-(N-acetoxycarbamimidoyl)phenoxy]pentanoicacid(2′-methansulfonylbiphenyl-4-yl)amide (36),

[0071]isobutyl(1-imino-1-{3-[1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate(37),

[0072]butyl(1-uimino-1-{3-[1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate(38),

[0073]isopropyl(1-imino-1-{3-[1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate(39),

[0074] 2-[3-(N-methoxycarbaminidoyl)phenoxy]pentanoicacid(2′-methansulfonylbiphenyl-4-yl)amide (40),

[0075] (S)-2-[3-(N-hydroxycarbaminidoyl)phenoxy]pentanoicacid(2′-methansulfonylbiphenyl-4-yl)amide (41),

[0076] (R)-2-[3-(N-hydroxycarbamimidoyl)phenoxy]pentanoicacid(2′-methansulfonylbiphenyl-4-yl)amide (42),

[0077]methyl(1-imino-1-{3-[(S)-1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate(43),

[0078] 2-(3-carbamimidoylphenoxy)pentanoicacid(2′-methansulfonylbiphenyl-2-ylmethyl)amide (44),

[0079]2-(3-carbamimidoylphenoxy)-N-(2′-methansulfonylbiphenyl-2-ylmethyl)-2-phenylacetamide(45),

[0080] 2-(3-carbamimidoylphenoxy)-4-methylpentanoicacid-(2′-methansulfonylbiphenyl-2-ylmethyl)amide (46),

[0081]4-(3-carbamimidoylphenoxy)-N-(2′-methansulfonylbiphenyl-4-yl)butyramide(47),

[0082]2-(7-carbamimidoyinaphthalin-2-yloxy)-N-(2′-methansulfonylbiphenyl-4-yl)-2-phenylacetamide(48),

[0083]3-(3-carbamimidoylphenoxy)-N-(2′-methansulfonylbiphenyl-4-yl)propionamide(49),

[0084] 2-(3-carbamimidoylphenyl)pentanoicacid(2′-methansulfonylbiphenyl-4-yl)amide (50),

[0085]4-(3-carbamimidoylphenyl)-N-(2′-methansulfonylbiphenyl-4-yl)butyramide(51),

[0086]3-[3-(N-hydroxycarbamimidoyl)phenyl]-N-(2′-methansulfonylbiphenyl-4-yl)propionamide(52),

[0087] 2-(3-carbamimidoylphenoxy)pentanoicacid(3-fluor-2′-methansulfonylbiphenyl-4-yl)amide (53).

[0088] The FAB values of these compounds are listed in the followingtables. If not stated otherwise, the compounds were in each caseprepared as acetates. TABLE 1 Measured FAB values of synthesized activecompounds

No. R⁵ A FAB 1 —H —CH₃ 424 2

—CH₃ 466 3

—CH₃ 466 4

—CH₃ 466 5

—CH₃ 466 6

480 7

—CH₃ 480 8

—CH₃ 494 9

—CH₃ 466 10 

—CH₃ 480 11 

—CH₃ 450 12 

514 13

—CH₃ 544 14

—CH₃ 528

[0089] TABLE 2 Measured FAB values of synthesized active compounds

Nr R⁵ A FAB 18 —H —CH₃ 422 19

—CH₃ 464 20

—CH₃ 489 21

512 22

542 23

—CH₃ 512 24

526 25

—CH₃ 450 26

—CH₃ 478 27

—CH₃ 478

[0090] TABLE 3 Measured FAB values of synthesized active compounds No.R⁵ A FAB 15

—CH₃ 480 16

—CH₃ 494 17

—CH₃ 514

[0091] TABLE 4 Measured FAB values of synthesized active compounds

Nr R¹ R⁵ R² FAB 28

524 29

418 30

482 31

—CF₃ 456 32

538 33

566 34

552 35

586 36

524 37

566 38

566 39

552 40

496 41

482 42

482 43

524

[0092] TABLE 5 Measured FAB valves of synthesized acitve compounds

Nr. R⁵ FAB 44

480 45

514 46

494

[0093] TABLE 6 Measured FAB valves of synthesized active compounds Nr.Struktur FAB 47

452 48

550 49

538 50

450 51

436 52

438 53

484

[0094] The invention further relates to the use of the compounds of theformula I and/or their physiologically acceptable salts for theproduction of pharmaceutical preparations, in particular in anon-chemical way. In this connection, they can be brought into asuitable dose form together with at least one solid, liquid and/orsemi-liquid vehicle or excipient and, if appropriate, in combinationwith one or more further active compounds.

[0095] The invention further relates to pharmaceutical preparationscomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts.

[0096] These preparations can be used as medicaments in human orveterinary medicine. Suitable vehicles are organic or inorganicsubstances which are suitable for enteral (e.g. oral) or parenteraladministration or topical application and do not react with the novelcompounds, for example water, vegetable oils, benzyl alcohols, alkyleneglycols, polyethylene glycols, glyceryl triacetate, gelatine,carbohydrates such as lactose or starch, magnesium stearate, talc andpetroleum jelly. In particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops are used for oraladministration, suppositories are used for rectal administration,solutions, preferably oily or aqueous solutions, furthermoresuspensions, emulsions or implants, are used for parenteraladministration, and ointments, creams or powders are used for topicalapplication. The novel compounds can also be lyophilized and thelyophilizates obtained used, for example, for the production ofinjection preparations. The preparations indicated can be sterilizedand/or can contain excipients such as lubricants, preservatives,stabilizers and/or wetting agents, emulsifiers, salts for influencingthe osmotic pressure, buffer substances, colorants, flavourings and/orone or more further active compounds, e.g. one or more vitamins.

[0097] The compounds of the formula I and their physiologicallyacceptable salts can be used in the control and prevention ofthromboembolic conditions such as thrombosis, myocardial infarct,arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosisafter angioplasty and intermittent claudication.

[0098] In this case, the substances according to the invention are as arule preferably administered in doses of between approximately 1 and 500mg, in particular between 5 and 100 mg, per dose unit. The daily dose ispreferably between approximately 0.02 and 10 mg/kg of bodyweight. Thespecific dose for each patient depends, however, on all sorts offactors, for example on the efficacy of the specific compound employed,on the age, bodyweight, general state of health, sex, on the diet, onthe time and route of administration, on the excretion rate,pharmaceutical combination and severity of the particular condition towhich the therapy applies. Oral administration is preferred.

[0099] The compounds of the formula I and also the starting substancesfor their preparation are prepared by methods known per se, such as aredescribed in the literature (e.g. in the standard works such asHouben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag,Stuttgart (Methods of Organic Chemistry)), namely under reactionconditions which are known and suitable for the reactions mentioned. Usecan also be made in this case of variants which are known per se but notmentioned here in greater detail.

[0100] If desired, the starting substances can also be formed in situ,such that they are not isolated from the reaction mixture, butimmediately reacted further to give the compounds of the formula I. Inthe following, a synthesis is generally presented with which compoundsof the formula I can be prepared. For the preparation of specificcompounds, the synthesis can be varied by the choice of suitablestarting compounds. The synthesis is only intended to show, by way ofexample, one possible route for the preparation of the compounds of theformula I. It is also possible, however, to use other synthetic routesfor preparation.

[0101] An examplary synthesis is shown in FIG. 1.

[0102] The protected acid unit A is reacted with the amine B, withformation of a central amide bond, to form the compound C. Thecarbamimidoyl group is then liberated reductively to give the inventivecompound D.

[0103] The acid unit A and the amine B are likewise preparable by commonsyntheses. An exemplary synthesis is presented below in FIG. 2.

[0104] For the synthesis of the acid unit, the phenol derivative Eprotected on the carbamimidoyl group is reacted with the protectedα-bromocarboxylic acid F to give the compound G. The ester G is thenhydrolysed to the carboxylic acid A′.

[0105] The amines B can be prepared, for example, in the following way(FIG. 3).

[0106] Bromonitrobenzene H is reacted with the boronic acid derivative Ito give the biphenyl derivative J. The methylthio group of the biphenylderivative I is then reacted with a suitable oxidizing agent such assodium perborate to give the methanesulfonyl compound K. In a furtherstep, the nitro group is reduced to the amine with attainment of theamine unit B′. According to an analogous synthesis route, it is alsopossible to prepare the corresponding ethanesulfonyl compounds (FIG. 4).

[0107] 2-Bromothiophenol is alkylated with iodoethane to give thecorresponding thioethane L. Conversion into the boronic acid M thentakes place and is followed, as already in the synthesis from FIG. 3, bythe linkage of a carbon bond to the biphenyl derivative N. The oxidationto the ethanesulfonyl compound is carried out and is followed by thereduction of the nitro group to the amine derivative B″. The preparationof a biphenylamine which comprises a CF₃ group can be carried out byappropriate choice of the starting materials analogously to thesyntheses shown in FIGS. 3 and 4. The synthesis is shown in FIG. 5.

[0108] The synthesis of the methoxy derivative, which is shown in FIG.6, also proceeds analogously.

[0109] The methylamine derivatives of the biphenyl moiety can beprepared from the corresponding nitrile compounds. An exemplarysynthesis is shown in FIG. 7.

[0110] The synthesis of active compounds having a modified carbamimidoylgroup is shown by way of example in FIGS. 8 and 9.

[0111] The synthesis routes shown can be easily varied by the personskilled in the art, for example by suitably modifying the substitutionpattern of the individual synthesis units.

[0112] The invention is illustrated in greater detail with the aid ofexamples.

EXAMPLE 1 [3-(5-Methyl[1,2,4]oxadiazol-3-yl)phenoxy]-2-phenylacetic acid

[0113] a)Methyl[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenoxy]-2-phenylacetate

[0114] A solution of 1.00 g (5.68 mmol) of3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenoxy]-2-phenol and 0.90 ml (5.7mmol) of methyl 2-bromo-2-phenylacetate in 20 ml of acetonitrile istreated with 1.96 g (6.00 mmol) of caesium carbonate and stirred at roomtemperature for 18 hours. The reaction mixture is filtered and thefiltrate is evaporated. A colourless solid is obtained; FAB 325.

[0115] b) [3-(5-Methyl[1,2,4)]oxadiazol-3-yl)phenoxy]-2-phenylaceticacid

[0116] A solution of 1.77 g (5.46 mmol) of methyl[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenoxy]-2-phenylacetate in 15 ml ofmethanol is treated with 10 ml of 1 N aqueous sodium hydroxide solutionand heated at 80° C. for 3 hours. The reaction mixture is concentratedand the residue is treated with 1 N hydrochloric acid. It is extractedwith ethyl acetate and the organic phase is evaporated. A colourlesssolid is obtained; FAB 311

EXAMPLE 2 2′-Methanesulfonylbiphenyl-4-ylamine

[0117] a) 2-Methylsulfanyl-4′-nitrobiphenyl

[0118] A solution of 30.3 g (150 mmol) of 1-bromo-4-nitrobenzene and25.0 g (149 mmol) of 2-methylthiobenzeneboronic acid in a mixture of 300ml of methanol and 500 ml of toluene is treated with 16.0 g (150 mmol)of sodium carbonate and 5.0 g (4.3 mmol) oftetrakis(triphenylphosphine)palladium and heated at 100° C. for 18hours. The reaction mixture is partitioned between water and ethylacetate, the organic phase is dried and evaporated and the residue isrecrystallized from petroleum ether/ethyl acetate. A yellowish solid isobtained; FAB 246

[0119] b) 2-Methanesulfonyl-4′-nitrobiphenyl

[0120] A solution of 20.0 g (81.5 mmol) of2-methylsulfanyl-4′-nitrobiphenyl in 150 ml of glacial acetic acid istreated with 66 g of sodium perborate trihydrate and heated at 60° C.with stirring for 3 days. The reaction mixture is added to water, andthe precipitate is filtered off and recrystallized from petroleumether/ethyl acetate. A yellowish solid is obtained; FAB 278

[0121] c) 2′-Methanesulfonylbiphenyl-4-ylamine

[0122] A solution of 17.0 g (61.3 mmol) of2-methanesulfonyl-4′-nitrobiphenyl in 170 ml of THF is treated with 3.5g of THF-moist Raney nickel and hydrogenated at room temperature andnormal pressure until the completion of hydrogen absorption (18 hours).The catalyst is filtered off and the filtrate is evaporated. Acolourless solid is obtained; FAB 248

EXAMPLE 3 2′-Ethanesulfonylbiphenyl-4-ylamine

[0123] a) 1-Bromo-2-ethylsulfanyl-1-benzene

[0124] A solution of 10 ml (85 mmol) of 2-bromothiophenol and 6.9 ml (85mmol) of iodoethane in 50 ml of acetonitrile is treated with 28 g (85mmol) of caesium carbonate and stirred at room temperature for 18 hours.The reaction mixture is filtered and the filtrate is evaporated. FAB218

[0125] b) 2-Ethylsulfanylbenzeneboronic acid

[0126] 9.5 g (50 mmol) of triisopropyl borate are added to a solution of10.9 g (50.0 mmol) of 1-bromo-2-ethylsulfanylbenzene kept at −70° C.33.3 ml of a 15% solution of BuLi in hexane (55 mmol) are then added.The mixture is stirred at −70° C. for a further 30 minutes, then 1 Nhydrochloric acid and ethyl acetate are added. The organic phase isseparated off, dried and evaporated. The residue is taken up in diethylether and filtered. A colourless solid is obtained; FAB 182

[0127] Further synthesis follows Example 2.

EXAMPLE 4 C-(2′-Methanesulfonylbiphenyl-4-yl)methylamine

[0128] a) 2′-Methanesulfonylbiphenyl-4-carbonitrile

[0129] A solution of 1.0 g (4.9 mmol) of 2-bromothioanisole and 1.5 g(10 mmol) of 4-cyanobenzeneboronic acid in a mixture of 50 ml of tolueneand 30 ml of methanol is treated with 1.1 g (10 mmol) of sodiumcarbonate and 0.5 g (0.43 mmol) of tetrakis(triphenylphosphine)palladiumand heated at 100° C. for 18 hours. The reaction mixture is partitionedbetween water and ethyl acetate. The organic phase is evaporated andchromatographed on a silica gel column using petroleum ether/ethylacetate. A colourless solid is obtained; FAB 226

[0130] b) 2′-Methanesulfonylbiphenyl-4-carbonitrile

[0131] A solution of 1.0 g (4.4 mmol) of2′-methanesulfonylbiphenyl-4-carbonitrile in 10 ml of glacial aceticacid is treated with 3.2 g of sodium perborate trihydrate and stirred atroom temperature for 48 hours. The reaction mixture is added to waterand the precipitate is filtered off. A colourless solid is obtained; FAB258

[0132] c) C-(2′-Methanesulfonylbiphenyl-4-yl)methylamine

[0133] A solution of 1.0 g (3.9 mmol) of2′-methanesulfonylbiphenyl-4-carbonitrile in a mixture of 10 ml ofmethanol saturated with ammonia and 3 ml of THF is treated with 400 mgof Raney nickel and hydrogenated at room temperature and normalpressure. The catalyst is filtered off and the filtrate is evaporated. Acolourless solid is obtained; FAB 262

EXAMPLE 52-(3-Carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)-2-phenylacetamide

[0134] a)N-(2′-Methanesulfonylbiphenyl-4-yl)-2-[3-(5-methyl[1,2,4]oxadiazol-3-yl)phenoxy]2-phenylacetamide

[0135] A solution of 102 mg (0.330 mmol) of[3-(5-methyl[1,2,4)]oxadiazol-3-yl)phenoxy]-2-phenylacetic acid, 81.6 mg(0.330 mmol) of 2′-methanesulfonylbiphenyl-4-ylamine, 63.3 mg (0.330mol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(DAPECI) and 44.6 mg (0.330 mmol) of 1-hydroxybenzotriazole (HOBt) in 5ml of DMF is treated with 0.036 ml (0.33 mmol) of 4-methylmorpholine andstirred at room temperature for 18 hours. The reaction mixture is addedto water and the precipitate is filtered off. A colourless solid isobtained; FAB 540

[0136] b)2-(3-Carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)-2-phenylacetamideacetate (11)

[0137] A solution of 150 mg (0.278 mmol) ofN-(2′-methanesulfonylbiphenyl-4-yl)-2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenoxy]-2-phenylacetamidein 7 ml of methanol is treated with 100 mg of water-moist Raney nickeland 70 mg of acetic acid and hydrogenated for 18 hours at roomtemperature and normal pressure. The reaction mixture is filtered, thefiltrate is evaporated and the residue is stirred with diethyl ether. Acolourless solid is obtained; FAB 500

EXAMPLE 6 2-[3-(N-Hydroxycarbamimidoyl)phenoxy]pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide hydrochloride (27)

[0138] a) Ethyl 2-(3-cyanophenoxy)pentanoate

[0139] A solution of 5.0 g (42 mmol) of 3-hydroxybenzonitrile and 8.78 g(42.0 mmol) of ethyl 2-bromovalerate in 80 ml of acetonitrile is treatedwith 13.7 g (42.0 mmol) of caesium carbonate and stirred at roomtemperature for 18 hours. The reaction mixture is filtered off and thefiltrate evaporated. A colourless oil is obtained; FAB 248

[0140] b) 2-(3-Cyanophenoxy)pentanoic acid

[0141] A solution of 9.00 g (36.5 mmol) of ethyl2-(3-cyanophenoxy)pentanoate in 10 ml of methanol is treated with asolution of 1.29 g (54.0 mmol) of lithium hydroxide in 10 ml of waterand the mixture is stirred at room temperature for 18 hours. Thereaction mixture is concentrated in vacuo, extracted with ethyl acetate,and the aqueous phase is acidified and extracted with ethyl acetate. Theorganic phase is dried over sodium sulfate and evaporated. A colourlesssolid is obtained; FAB 220

[0142] c) 2-(3-Cyanophenoxy)pentanoic acid)(2′-methanesulfonylbiphenyl-4-yl)amide

[0143] A solution of 2.26 g (9.12 mmol) of2′-methanesulfonylbiphenyl-4-ylamine, 2.00 g (9.12 mmol) of2-(3-cyanophenoxy)pentanoic acid, 1.75 g (9.12 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.23 g(9.12 mmol of 1-hydroxybenzotriazole and 1.00 ml (9.12 mmol) of4-methylmorpholine in 5 ml of DMF is stirred at room temperature for 18hours. The reaction mixture is treated with water and the resultingprecipitate is filtered off. A colourless solid is obtained; FAB 449

[0144] d) 2-[3-(N-Hydroxycarbamimidoyl)phenoxy]pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide

[0145] A solution of 1.40 g (3.12 mmol) of 2-(3-cyanophenoxy)pentanoicacid (2′-methanesulfonylbiphenyl-4-yl)amide in 50 ml of methanol istreated with 695 mg (10.0 mmol) of hydroxylammonium chloridehydrochloride and 1.01 g (10.0 mmol) of triethylamine and stirred at 60°C. for 18 hours. It is allowed to cool, the solvent is stripped off, theresidue is taken up in water and the resulting precipitate is filteredoff. A colourless solid is obtained; FAB 482

[0146] e) 2-[3-(N-Hydroxycarbamimidoyl)phenoxy]pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide hydrochloride (27)

[0147] A solution of 100 mg (0.208 mmol) of2-[3-(N-hydroxycarbamimidoyl)phenoxy]pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide in 5 ml of methanol is treatedwith 2.08 ml of a 0.1 N solution of hydrogen chloride in isopropanol.The solution is evaporated. A colourless solid is obtained; FAB 482

EXAMPLE 7methyl(1-imino-1-{3-[1-(2′-methanesulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate

[0148] 1 N NaOH is added up to a pH of 9 to a solution of 500 mg (1.07mmol) of 2-(3-carbamimidoylphenoxy) pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide acetate (3) in 40 ml ofdichloromethane kept at 5° C. 0.108 ml (1.40 mmol) of methylchloroformate is then added. During the following hour, the pH is keptat a value of 9 by addition of further 1 N NaOH. The organic phase isthen separated off, washed with water, dried over sodium sulfate andevaporated. A colourless solid is obtained; FAB 524

[0149] The following examples relate to pharmaceutical preparations.

EXAMPLE A Injection Vials

[0150] A solution of 100 g of an active compound of the formula I and 5g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l ofdouble-distilled water using 2 N hydrochloric acid, sterile filtered,dispensed into injection vials, lyophilized under sterile conditions andaseptically sealed. Each injection vial contains 5 mg of activecompound.

EXAMPLE B Suppositories

[0151] A mixture of 20 g of an active compound of the formula I is fusedwith 100 g of soya lecithin and 1400 g of cocoa butter, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activecompound.

EXAMPLE C Solution

[0152] A solution is prepared from 1 g of an active compound of theformula I, 9.38 g of NaH₂PO₄ 2 H₂O, 28.48 g of Na₂HPO₄ 12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of double-distilled water. It isadjusted to pH 6.8, made up to 1 l and sterilized by irradiation. Thissolution can be used in the form of eye drops.

EXAMPLE D Ointment

[0153] 500 mg of an active compound of the formula I are mixed with 99.5g of petroleum jelly under aseptic conditions.

EXAMPLE E Tablets

[0154] A mixture of 1 kg of active compound of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is compressed in a customary manner to give tablets such thateach tablet contains 10 mg of active compound.

EXAMPLE F Coated tablets

[0155] Analogously to Example E, tablets are pressed and are then coatedin a customary manner with a coating of sucrose, potato starch, talc,tragacanth and colorant.

EXAMPLE G Capsules

[0156] 2 kg of active compound of the formula I are filled into hardgelatine capsules in a customary manner such that each capsule contains20 mg of the active compound.

EXAMPLE H Ampoules

[0157] A solution of 1 kg of active compound of the formula I in 60 l ofdouble-distilled water is sterile filtered, dispensed into ampoules,lyophilized under sterile conditions and aseptically sealed. Eachampoule contains 10 mg of active compound.

1: A compound of the formula I

in which: R¹ is: phenyl or naphthyl, which is substituted by —C(═NH)NH₂,that is optionally monosubstituted by —COA, —CO[C(R⁷)₂]_(n)—Ar′, —COOA,—OR⁷, —OCOA, —OCO—[C(R⁷)₂]_(n)—Ar′, —OH, an amino protective group,—NHC(═NH)—NH₂, —CON═C(NH₂)₂,

and which is optionally substituted by -A, —OR⁵, —N(R⁵)₂, —NO₂, —CN,-Hal, —NR⁵COA, —NR⁵COAr′, —NR⁵SO₂A, —NR⁵SO₂Ar′, —COOR⁵, —CON(R⁵)₂,—COR⁷, —COAr′ or S(O)_(n)A; R² is: —S(O)_(n)A, —CF₃, —COOR⁷, or —OA; R³,R⁴ are: independently of one another —H, -A, —OR⁵, —N(R⁵)₂, —NO₂, —CN,-Hal, —NR⁵COA, —NR⁵COAr′, —NR⁵SO₂A, —NR⁵SO₂Ar′, —COOR⁵, —CON(R⁵)₂,—CONR⁵Ar′, —COR⁷, —COAr′, or —S(O)_(n)A; R⁵, R⁶ are: independently ofone another —H, -A, —[C(R⁷R⁸)]_(n)Ar′ or —[C(R⁷R⁸)]_(n)Het; R⁷, R⁸ are:independently of one another —H or -A; W is:—[C(R⁵R⁶)]_(m)CONR⁵[C(R⁵R⁶)]_(l)—, or —OC(R⁵R⁶)CONR⁵[C(R⁵R⁶)]_(l)—; Ais: alkyl having 1 to 20 C atoms, in which one or two CH₂ groups areoptionally and independently replaced by O or S atoms or by —CH═CH—groups and wherein 1 to 7 H atoms are optionally replaced by —F; Ar is:phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by -A, —Ar′—, -Het, —OR⁵, —N(R⁵)₂, —NO₂, —CN, -Hal,—NR⁵COA, —NR⁵COAr, —NR⁵SO₂A, —NR⁵SO₂Ar′, —COOR⁵, —CON(R⁵)₂, —CONR⁵Ar′,—COR⁷, —COAr′, —SO₂NR⁵, —S(O)_(n)Ar′ or —S(O)_(n)A; Ar′ is: phenyl ornaphthyl, which is unsubstituted or mono-, di- or trisubstituted by -A,—OR⁷, —N(R⁷)₂, —NO₂, —CN, -Hal, —NR⁷COA, —NR⁷SO₂A, —COOR⁷, —CON(R⁷)₂,—COR⁷, —SO₂NR⁷ or —S(O)_(n)A; Het is: a mono- or binuclear saturated,unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms,bonded via N or C, which is unsubstituted or mono-, di- ortrisubstituted by -A, —OR⁷, —N(R⁷)₂, —NO₂, CN, -Hal, —NR⁷COA, —NR⁷SO₂A,—COOR⁷, —CON(R⁷)₂, —COR⁷, SO₂NR⁷, —S(O)_(n)A and/or carbonyl oxygen; Halis: —F, —Cl, —Br or —I; l is: 0 or 1; m is: 1, 2 or 3; and n is: 0, 1 or2; or a pharmaceutically acceptable salt or solvate thereof. 2: Acompound according to claim 1, selected from the following compounds2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)acetamide(1),2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)butyramide(2), 2-(3-carbamimidoylphenoxy)pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (3),(S)-2-(3-carbamimidoylphenoxy)pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (4),(R)-2-(3-carbamimidoylphenoxy)pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (5),(2-(3-carbamimidoylphenoxy)pentanoic acid(2′-ethanesulfonylbiphenyl-4-yl)amide (6),(2-(3-carbamimidoylphenoxy)hexanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (7),(2-(3-carbamimidoylphenoxy)hexptanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (8),2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)-3-methylbutyramide(9), 2-(3-carbamimidoylphenoxy)-4-methylpentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (10),2-(3-carbamimidoylphenoxy)-4-methylpentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (11),2-(3-carbamimidoylphenoxy)-N-(2′-ethanesulfonylbiphenyl-4-yl)-2-phenylacetamide(12),2-(1,3-benzodioxol-5-yl)-2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)acetamide(13),2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-yl)-4-phenylbutyramide(14), 2-(3-carbamimidoylphenoxy)pentanoic acid(2′-methanesulfonylbiphenyl-4-ylmethyl)amide (15),2-(3-carbamimidoylphenoxy)4-methylpentanoic acid(2′-methanesulfonylbiphenyl-4-ylmethyl)amide (16);2-(3-carbamimidoylphenoxy)-N-(2′-methanesulfonylbiphenyl-4-ylmethyl)-2-phenylacetamide(17),3-(3-carbamimidoylphenyl)-N-(2′-methanesulfonylbiphenyl-4-yl)propionamide(18), 2-(3-carbamimidoylbenzyl)pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (19),3-(3-carbamimidoylphenyl)-N-(2′-methanesulfonylbiphenyl-4-yl)-2-phenylpropionamide(20),3-(3-carbamimidoylphenyl)-N-(2′-ethanesulfonylbiphenyl-4-yl)-2-phenylpropionamide(21),3-(3-carbamimidoylphenyl)-N-(2′-ethanesulfonylbiphenyl4-yl)-2-(3-methoxyphenyl)propionamide(22),2-benzyl-3-(3-carbamimidoylphenyl)-N-(2′-methanesulfonylbiphenyl-4-yl)propionamide(23),2-benzyl-3-(3-carbamimidoylphenyl)-N-(2′-ethanesulfonylbiphenyl-4-yl)propionamide(24),2-(3-carbaminidoylbenzyl)-N-(2′-methanesulfonylbiphenyl-4-yl)butyramide(25), 2-(3-carbaminidoylbenzyl)hexanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (26),2-(3-carbamimidoyl)-4-methylpentanoicacid(2′-methanesulfonylbiphenyl-4-yl)amide (27),methyl(1-imino-1-(3-(1-(2′-methanesulfonylbiphenyl-4-ylcarbamoyl)butoxy)phenyl)methyl)carbamate(28), 2-(3-carbamimidoylphenoxy)pentanoic acid(2′-methoxybiphenyl-4-yl)amide (29),2-[3-(N-hydroxycarbamimidoyl)phenoxy]pentanoic acid(2′-methanesulfonylbiphenyl-4-yl)amide (30),2-(3-carbamimidoylphenoxy)pentanoic acid(2′-trifluoromethylbiphenyl-4-yl)amide (31),ethyl(1-imino-1-{3-[1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)-butoxy]phenyl}methyl)carbamate(32), 2-[3-(N-pentanoyloxycarbamimidoyl)phenoxy]pentanoicacid-(2′-methansulfonylbiphenyl-4-yl)amide (33),2-[3-(N-(2-methylpropionyloxy)carbamimidoyl)phenoxyl]pentanoic acid(2′-methansulfonylbiphenyl-4-yl)amide (34),2-[3-(N-benzoyloxycarbamimidoyl)phenoxyl]pentanoic acid(2′-methansulfonylbiphenyl-4-yl)amide (35),2-[3-(N-acetoxycarbamimidoyl)phenoxy]pentanoicacid(2′-methansulfonylbiphenyl-4-yl)amide (36),isobutyl(1-imino-1-{3-[1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate(37),butyl(1-uimino-1-{3-[1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate(38),isopropyl(1-imino-1-{3-[1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate(39), 2-[3-(N-methoxycarbaminidoyl)phenoxy]pentanoicacid(2′-methansulfonylbiphenyl-4-yl)amide (40),(S)-2-[3-(N-hydroxycarbaminidoyl)phenoxy]pentanoic acid(2′-methansulfonylbiphenyl-4-yl)amide (41),(R)-2-[3-(N-hydroxycarbamimidoyl)phenoxy]pentanoic acid(2′-methansulfonylbiphenyl-4-yl)amide (42),methyl(1-imino-1-{3-[(S)-1-(2′-methansulfonylbiphenyl-4-ylcarbamoyl)butoxy]phenyl}methyl)carbamate(43), 2-(3-carbamimidoylphenoxy)pentanoicacid(2′-methansulfonylbiphenyl-2-ylmethyl)amide (44),2-(3-carbamimidoylphenoxy)-N-(2′-methansulfonylbiphenyl-2-ylmethyl)-2-phenylacetamide(45), 2-(3-carbamimidoylphenoxy)-4-methylpentanoicacid-(2′-methansulfonylbiphenyl-2-ylmethyl)amide (46),4-(3-carbamimidoylphenoxy)-N-(2′-methansulfonylbiphenyl-4-yl)butyramide(47),2-(7-carbamimidoylnaphthalin-2-yloxy)-N-(2′-methansulfonylbiphenyl-4-yl)-2-phenylacetamide(48),3-(3-carbamimidoylphenoxy)-N-(2′-methansulfonylbiphenyl-4-yl)propionamide(49), 2-(3-carbamimidoylphenyl)pentanoicacid(2′-methansulfonylbiphenyl-4-yl)amide (50),4-(3-carbamimidoylphenyl)-N-(2′-methansulfonylbiphenyl-4-yl)butyramide(51),3-[3-(N-hydroxycarbamimidoyl)phenyl]-N-(2′-methansulfonylbiphenyl-4-yl)propionamide(52), 2-(3-carbamimidoylphenoxy)pentanoicacid(3-fluor-2′-methansulfonylbiphenyl-4-yl)amide (53). 3 (Cancelled) 4:A method for treating thrombosis, myocardial infarct, arteriosclerosis,inflammation, apoplexy, angina pectoris, restenosis after angioplasty orintermittent claudication comprising administering to a patient in needthereof a pharmaceutical composition according to claim
 8. 5: A processfor preparing a pharmaceutical composition, comprising bringing togetherinto a dose form a compound according to claim 1 and/or one of itsphysiologically acceptable salts with at least one solid, liquid orsemi-liquid vehicle or excipient. 6: A method for inhibiting coagulationfactor Xa, comprising administering to a patient in need thereof apharmaceutical composition according to claim
 8. 7: A method forinhibiting coagulation factor VIIa, comprising administering to apatient in need thereof a pharmaceutical composition according to claim8. 8: A pharmaceutical composition comprising at least one compoundaccording to claim 1 or one of its physiologically acceptable salts, anda pharmaceutically acceptable vehicle or excipient. 9: A method fortreating thrombosis comprising administering to a patient in needthereof a pharmaceutical composition according to claim
 8. 10: Apharmaceutical composition comprising at least one compound according toclaim 2 or one of its physiologically acceptable salts, and apharmaceutically acceptable vehicle or excipient. 11: A method fortreating thrombosis, myocardial infarct, arteriosclerosis, inflammation,apoplexy, angina pectoris, restenosis after angioplasty or intermittentclaudication comprising administering to a patient in need thereof apharmaceutical composition according to claim
 10. 12: A method forinhibiting coagulation factor Xa, comprising administering to a patientin need thereof a pharmaceutical composition according to claim
 10. 13:A method for inhibiting coagulation factor VIIa, comprisingadministering to a patient in need thereof a pharmaceutical compositionaccording to claim
 10. 14: A method for treating thrombosis comprisingadministering to a patient in need thereof a pharmaceutical compositionaccording to claim
 10. 15: A process for preparing a pharmaceuticalcomposition, comprising bringing together into a dose form a compoundaccording to claim 2 and/or one of its physiologically acceptable saltswith at least one solid, liquid or semi-liquid vehicle or excipient. 16:A composition according to claim 1, wherein R¹ is phenyl substituted by—C(═NH)NH₂. 17: A composition according to claim 16, wherein —C(═NH)NH₂is monosubstituted by —COOA, —OCOA, —CO[C(R⁷)₂]_(n)—Ar′, —OA, or —OH.18: A composition according to claim 1 wherein R² is S(O)(O)A, —CF₃ orOA. 19: A composition according to claim 18, wherein R¹ is phenylsubstituted by —C(═NH)NH₂. 20: A composition according to claim 16,wherein R² is S(O)(O)A.